Neuropathic pain following nerve injury is a characteristic example of pathological pain. A major obstacle in treating neuropathic pain is its poor and unreliable responses to conventional analgesics. Recent studies indicate that the efficacy of cannabinoid-induced analgesia remains undiminished in a neuropathic pain state and that cannabinoids may be an effective alternative in attenuating neuropathic pain. The central actions of cannabinoid-induced analgesia are mainly mediated through the cannabinoid-1 receptor (CB1R). There is increasing evidence that CB1Rs within the spinal cord dorsal horn are upregulated following peripheral nerve injury, but the cellular mechanisms of CB1R upregulation and its relation to the analgesic effects of cannabinoids in a neuropathic pain state remain unclear. Based on the literature and our preliminary data, we hypothesize that peripheral nerve injury induces changes of spinal CB1Rs that are regulated by nerve injury-induced increases in spinal neurotrophic factors and glutamatergic activity as well as the related intracellular cascades, contributing to the therapeutic effects of cannabinoids in a neuropathic pain state. This central hypothesis will be investigated by utilizing the methods of behavioral and pharmacological evaluation, immunocytochemistry, Western blot, in situ hybridization, receptor autoradiography, and GTPgammaS binding assay in order to accomplish four specific aims: (1) to investigate the time course and topographic distribution of spinal CB1R changes in a neuropathic pain state; (2) to examine neuropathic pain-related changes of the CB1R function (autoradiographic receptor binding and GTPgammaS binding); (3) to investigate the role of spinal neurotrophic factors and glutamatergic activites as well as the related intracellular cascades in the regulation of CB1R changes in a neuropathic pain state; and (4) to evaluate the relationship between the spinal CB1R regulation and the therapeutic effects of cannabinoids on neuropathic pain. This proposed work would yield novel and important information regarding the cellular mechanisms of neuropathic pain modulation by cannabinoids. A better understanding of cannabinoid actions in neuropathic pain states could open a new avenue to developing novel pharmacological tools for the improved management of often intractable and debilitating neuropathic pain syndromes.